The present invention relates more specifically to the use of docetaxel in combination with recombinant humanized anti-HER2 antibody, rhuMAb HER2, for the treatment of cancers.
Selected term definitions are as follows:
"docetaxel" refers to the active ingredient of TAXOTERE.RTM. or else TAXOTERE.RTM. itself; PA1 "rhuMAb HER2," or trastuzumab, refers to the active ingredient of HERCEPTIN.RTM. or else HERCEPTIN.RTM. itself; PA1 "HER2" refers to human epidermal growth factor 2, a 185 kD transmembrane glycoprotein receptor (p185.sup.HER2); and PA1 "drug" or "drugs" refers to the above-mentioned active ingredients or medicaments or pharmaceutical preparations containing them.
Previous researchers have noted that docetaxel (TAXOTERE.RTM.) and its derivatives (such as TAXOL.RTM., paclitaxel) are useful in the treatment of the malignant neoplasms, such as solid tumors and other malignancies. European Patent EP 0 253 738 and International Patent Application WO 92/09589 describe a method of preparation of docetaxel. Generally, the doses, which vary depending on the patient, comprise between 60 and 400 mg/m.sup.2 of docetaxel. Commonly, docetaxel is administered via intravenous route at doses of 60 to 100 mg/m.sup.2 over 1 hour every 3 weeks (Textbook of Medical Oncology, Franco Cavelli et al., Martin Dunitz Ltd., p. 4623 (1997)).
Many clinical studies have confirmed the efficacy of docetaxel in treating many types of cancer, particularly breast cancer. Docetaxel's effects are shown in both first and second line therapies. The mechanism of docetaxel's action is thought to be via enhancement of microtubule assembly and inhibition of the depolymerization of tubulin at the cellular level.
The humanized recombinant monoclonal antibody rhuMAb HER2 (Trastuzumab, HERCEPTIN.RTM., Genentech) has also been found to be active in treatment of cancers that express HER2. A gene known as neu, or c-erbB-2, encodes the human epidermal growth factor receptor 2, known as HER2. HER2 is a transmembrane receptor tyrosine kinase with partial homology with the epidermal growth factor receptor, both of which receptors belong to the type 1 tyrosine kinase receptor superfamily. About 30% of human breast tumors overexpress HER2. Such overexpression is associated with a poor prognosis. rhuMAb HER2 inhibits the growth of breast cancer cells overexpressing HER2 and has shown some clinical activity as a single agent.
It has also been described that rhuMAb HER2 enhances the antitumor activity of chemotherapeutic agents against HER2/neu overexpressing human breast cancer xenografts (Baselga et al., Cancer Research, 58, 2825-2831, Jul. 1, 1998), but this result was based solely on preclinical animal models.
Further, both treatments, taxotere and rhuMAb HER2, used alone can have disturbing side effects. All treatments based on taxoid derivatives, including docetaxel, can show serious and troubling toxicities, such as myelosuppression, neutropenia, hypersensitivity, peripheral neuropathy, and fluid retention, among others (Fumoleau et al., Bull. Cancer, (82)8: 629-636 (1995)). While neutropenia, alopecia and mucositis are rarely caused by treatment with rhuMAb HER2, that drug has been shown to be associated with cardiac dysfunction. When such toxicities appear, dosages of the drugs must be limited with a resulting limitation on the efficacy of the treatment.
Consequently, there is an unmet need in the art for pharmaceutical preparations and methods of treating cancer which enhance the activity of docetaxel and rhuMAb HER2 without increasing the amount of the dosages administered and without increasing adverse side effects.